title: RLIP76 protein knockdown attenuates obesity due to a high-fat diet.
abstract: Feeding a Western high-fat diet (HFD) to C57BL/6 mice induces obesity, associated with a chronic inflammatory state, lipid transport, and metabolic derangements, and organ system effects that particularly prominent in the kidneys. Here, we report that RLIP76 homozygous knock-out (RLIP76(-/-)) mice are highly resistant to obesity as well as these other features of metabolic syndrome caused by HFD. The normal increase in pro-inflammatory and fibrotic markers associated with HFD induced obesity in wild-type C57B mice was broadly and nearly completely abrogated in RLIP76(-/-) mice. This is a particularly striking finding because chemical markers of oxidative stress including lipid hydroperoxides and alkenals were significantly higher in RLIP76(-/-) mice. Whereas HFD caused marked suppression of AMPK in wild-type C57B mice, RLIP76(-/-) mice had baseline activation of AMP-activated protein kinase, which was not further affected by HFD. The baseline renal function was reduced in RLIP76(-/-) mice as compared with wild-type, but was unaffected by HFD, in marked contrast to severe renal impairment and glomerulopathy in the wild-type mice given HFD. Our findings confirm a fundamental role of RLIP76 in regulating the function of obesity-promoting pro-inflammatory cytokines, and provide a novel mechanism for targeted therapy of obesity and metabolic syndrome.
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Comprehensive Cancer Center, Duarte, California 91010, USA.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.forename: James
authors.initials: J
authors.lastname: Figarola
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.forename: Marpadga A
authors.initials: MA
authors.lastname: Reddy
authors.forename: Xueli
authors.initials: X
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Berz
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004041:Dietary Fats; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Adiponectin; Adipose Tissue; Insulin; Kidney; Leptin; Obesity